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NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression

Jennifer L Larson-Casey1, Linlin Gu1, Jungsoon Kang1

  • 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The Journal of Biological Chemistry
|May 23, 2021
PubMed

Insights

Pulmonary fibrosis, like asbestosis, involves lung macrophages resisting cell death. This study identifies NADPH oxidase 4 (NOX4) as key to this resistance, suggesting NOX4 as a therapeutic target for lung fibrosis.

Area of Science:

  • Pulmonary medicine
  • Cell biology
  • Toxicology

Background:

  • Pulmonary fibrosis is a progressive lung disease often linked to environmental exposures like asbestos.
  • Asbestos-induced lung fibrosis (asbestosis) involves lung macrophages that resist apoptosis, but the mechanism is unclear.
  • Macrophages generate reactive oxygen species (ROS) and resist apoptosis, contributing to asbestosis pathogenesis.

Purpose of the Study:

  • To investigate the mechanism of apoptosis resistance in macrophages from asbestosis patients.
  • To determine the role of NADPH oxidase 4 (NOX4) in macrophage apoptosis resistance and pulmonary fibrosis.
  • To explore NOX4 as a potential therapeutic target for pulmonary fibrosis.

Main Methods:

  • Analysis of macrophages from asbestosis subjects and chrysotile-exposed mice.
  • Assessment of mitochondrial NADPH oxidase 4 (NOX4) content and ROS generation.
  • Evaluation of apoptosis in wild-type and Nox4 knockout (Nox4-/-) mice macrophages.
  • Investigation of NOX4's role in apoptosis signaling pathways (Akt1, Bcl-2).
  • Utilizing conditional Nox4 deletion in monocyte-derived macrophages in mouse models of pulmonary fibrosis.

Main Results:

  • Macrophages from asbestosis subjects and chrysotile-exposed mice exhibit apoptosis resistance.
  • Enhanced mitochondrial NOX4 and ROS generation correlate with apoptosis resistance.
  • Nox4 deficiency in macrophages increases apoptosis and protects against pulmonary fibrosis.
  • NOX4 regulates apoptosis resistance via Akt1-mediated phosphorylation of Bcl-2-associated death protein.
  • Conditional deletion of Nox4 in macrophages prevents and resolves pulmonary fibrosis in mice.

Conclusions:

  • NADPH oxidase 4 (NOX4) plays a critical role in mediating apoptosis resistance in monocyte-derived macrophages.
  • NOX4 contributes significantly to the pathogenesis of asbestos-induced pulmonary fibrosis.
  • Targeting NOX4-mediated apoptosis resistance in macrophages presents a potential therapeutic strategy for pulmonary fibrosis.
Keywords:
NOX4apoptosis resistancemonocyte-derived macrophagespulmonary fibrosis

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